Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE). We will examine both candidate genes and circulating procoagulant activity to determine if they are associated with VTE. Our specific aims are: Aim 1: To identify functional SNPs/ht- SNPs within a large set candidate genes and test these SNPs/ht-SNPs for an association with VTE. Using high throughput genotyping of known gene-centric DMAvariants (n=5000), we will test a large set of candidate genes (n=300) within the anticoagulant, procoagulant, fibrinolytic, and acute systemic inflammation pathways. Linkage dysequilibrium will be used to identify haplotype-tagging SNPs within 1,500 clinic-based, idiopathic VTE cases from the Midwest, and 1500 unrelated controls frequency-matched on patient age, gender, and county of residence; Aim 2: To determine if complex candidate gene interactions are associated with VTE. Using data from aim 1, we will apply single SNP and haplotype analyses to identify specific variants and groups of variants associated with VTE. We will also investigate the joint effects of these susceptibility genes on VTE stratified on Factor V Leiden; and Aim 3: To determine if functional assays of circulating whole blood procoagulant activity associate with VTE, including genetic interactions. We will use global functional assays to prospectively test such activity for an association with VTE in a sample of our clinic-based VTE cases (n=300) and controls (n=600), including genetic interactions. VTE is a major national health problem, with over 275,000 incident cases per year in the United States and costing over $7.3 billion (in 1999 dollars) per year for treatment charges alone. Since one-quarter of PE patients present as sudden death, the incidence of VTE must be reduced in order to improve survival. However, the incidence of VTE has remained relatively constant at about 1 per 1000 since 1980. Clearly, better methods of targeting VTE prophylaxis are needed.